Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
This office action is in reply to the Applicant’s Arguments/Remarks filed 25 June 2026 for application 18/686,652 filed 26 February 2024. Claims 1 and 3 are amended. Claims 2 and 4 are canceled. Claims 5 and 6 are new. Currently, claims 1, 3 and 5-6 are pending.
REJECTIONS – MAINTAINED & NEW
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(New) Claim 6 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
A review of the rejected claim language indicates that this claim is drawn toward “a method of treating triple negative breast cancer (TNBC) with the compound as claimed in claim 5”. A description of the term "a method of treating or preventing a disease or disorder... may be achieved by means of a recitation of a representative number of species falling within the scope of the genus or of a recitation of structural features common to the members of the genus, which features constitute a substantial portion of the genus. Regents of the University of California V. Eli Lilly & Co., 119 F3d 1559, 1569, 43 USPQ2d 1398, 1406 (Fed. Cir. 1997). In Regents of the University of California V. Eli Lilly (43 USPQ2d 1398-1412), the court held that a generic statement which defines a genus of nucleic acids by only their functional activity does not provide an adequate written description of the genus. The court indicated that, while applicants are not required to disclose every species encompassed by a genus, the description of the genus is achieved by the recitation of a representative number of species falling within the scope of the claimed genus. At section B (1), the court states "An adequate written description of a DNA requires a precise definition, such as by structure, formula, chemical name, or physical properties, not a mere wish or plan for obtaining the claimed chemical invention". Hence, an adequate written description of the components requires more than a mere statement that it is part of the invention. The description requirement of the patent statue requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984).
In Applicant’s originally filed specification, the Applicant describes novel compounds of formula I that were evaluated for potential anticancer properties in triple negative breast cancer cells (MDA-MB-231). However, the Applicant only demonstrates application of the claimed structures in terms of in vitro cell survival. Applicant does not demonstrate that the product is capable of the claimed method of treatment of the various diseases of the claim limitations to the breadth and scope of which broadest reasonable interpretation requires. The limited in vitro data leads one to conclude that the Applicant was not in possession of a method of treating the disease listed. Cancer is a broad class of heterogenous diseases for which there exists no general treatment or prevention. Hanahan et al. (The hallmarks of cancer, Cell 2000, 100, 1, 50-70) teaches that “there are more than 100 distinct types of cancer and subtypes of tumors can be found within specific organs (pg. 1). It is an incredibly broad field encompassing numerous possibilities that are differentiated by target, types and subtypes, patient populations, etiologies, co-morbidities, etc. Dass et al. (Triple negative breast cancer: a review of present and future diagnostic modalities, Medicina 2021, 57, 62) teaches that for triple negative breast cancer (TNBC), there are two subtypes, basal-like and claudin-low, that not all TNBC are basal-like with only 70-80% categorized as being of that type, and that several other factors can cause TNBC including genetic, signaling pathways, obesity, menopause, multi-party, socioeconomic, and non-breastfeeding. Caludin-low breast cancers are characterized by limited expression of Ki-67 and luminal markers and elevated expression of CD14, CD79b and vav1 and genes involved in cancer stem cell features (pgs. 2-3). Furthermore, the non-Caludin-low breast cancers are further subtyped into six subtypes, immunomodulatory, luminal androgen receptor, basal-like 1, basl-like 2, mesenchymal and mesenchymal stem-like, categorized based on their gene expression. Doing so allows medical providers to identify treatment alternatives and establish personalized, targeted medications for individuals (pgs. 3-4 & table 1). These factors undermine the concept that in vitro cell survival results are prophetic to the final therapeutic application of the invention. Whether the specification shows that the inventor was in possession of the claimed invention is not a single, simple determination, but rather a factual determination reached by considering a number of factors. Factors to be considered in determining whether there is sufficient evidence of possession include the level of skill and knowledge in the art, partial structures, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. In contrast, for inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predicable which are known to one of ordinary skill in the art, more evidence is required to show possession. One of skill in the art would not recognize from the disclosure that the applicant was in possession of a “method of treatment” for the diseases as claimed.
Additionally, it is known that there are significant challenges translating biochemical, in vitro, and in vivo studies to a clinical setting, and that not all biochemical, in vitro, and in vivo studies can be directly translated to the clinical setting. Indeed, J. M. McKim (Building a tiered approach to in vitro predictive toxicity screening: a focus on assays with in vivo resistance, Combo. Chem. & High Throughput Scr. 2010, 13, 188-206) emphasizes a truism of the pharmaceutical industry that persists to this day, is the failure of over 90% of promising new drug candidates due to unanticipated adverse effects or a lack of efficacy in humans, contrary to anticipated results based on prior biochemical, cell, or animal models (introduction). As the specification discloses working examples only performed biochemically, one of skill in the art would not recognize that the Applicant was in possession of “a method of treatment” of the various diseases and conditions claimed in an in vivo, much less a clinical, setting.
(New) Claim 6 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for in vitro MDA-MB-231 cell killing, does not reasonably provide enablement for treating triple negative breast cancer in all possible scenarios. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. These factors include, but are not limited to: (A) The breadth of the claims; (B) The nature of the invention; (C) The state of the prior art; (D) The level of one of ordinary skill; (E) The level of predictability in the art; (F) The amount of direction provided by the inventor; (G) The existence of working examples; and (H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure. See MPEP § 2164.01(a).
Upon consideration of the factors discussed below, the examiner concludes that one skilled in the art could not practice the invention without being burdened with undue experimentation based on the information provided by the applicant. A discussion of these factors as they relate to the pending claims is as follows:
13. (A) Breadth of claims & (B) Nature of invention –
The Applicant’s claims are broad. Claim 6 is directed to a “method of treating triple negative breast cancer…”. While the Applicant discloses the potential application of the product in developing new therapies for cancer, it does not demonstrate applicability, to what is known to one of ordinary skill in the art, is an incredibly broad field encompassing numerous possibilities that are differentiated by target, types and subtypes, patient populations, etiologies, co-morbidities, etc. Cancer is a broad class of heterogenous diseases for which there exists no general treatment or prevention. Hanahan teaches that “there are more than 100 distinct types of cancer and subtypes of tumors can be found within specific organs (pg. 1). Dass teaches that TNBC can be further divided into other subtypes and that standard-of-care treatment must be curated and targeted to be efficacious (pg. 4). The lack of specificity as to what the patient is also paints an extremely broadly brush as it includes not only humans but any creature of whom this treatment may be relevant for, including mammals of which there are far too many examples to list here. As the specification discloses working examples only performed in an in vitro assay, one of ordinary skill in the art would not recognize that the evidence provided by the Applicant in the instant specification is “a method of treating triple negative breast cancer” considering the possible breadth of what is a diverse genus that can arise from multiple factors and pathways.
(C) The state of the prior art –
The state of the prior art provides evidence for the degree of predictability in the art and is related to the amount of direction or guidance needed in the specification as filed to meet the enablement requirement. The state of the prior art is also related to the need for working examples in the specification. See MPEP § 2164.05(a). To the best of the Examiner’s knowledge, there is no general pharmacological agent and/or pharmaceutical composition containing pharmacological agents capable of ubiquitously treating triple negative breast cancer. This is emphasized by Hanahan and Dass, characterizing cancer as a disease that is already “complex beyond measure” (pg. 1) and often requiring individual, tailored therapies. It is therefore reasonable to conclude that the current state of the art is highly unpredictable and extremely complex, indicating that more details, working examples, and guidance would be required to practice the invention as disclosed for treating cancer as claimed.
(D) The level of one of ordinary skill in the art –
MPEP 2141.03 states (in part), “A person of ordinary skill in the art is also a person of ordinary creativity, not an automaton.” KSR International Co. v. Teleflex Inc., 127 S.Ct. 1727, 167 LEd2d 705, 82 USPQ2d 1385, 1397 (2007). “[I]n many cases a person of ordinary skill will be able to fit the teachings of multiple patents together like pieces of a puzzle.” Id. Office personnel may also take into account “the inferences and creative steps that a person of ordinary skill in the art would employ.” Id. At 1396, 82 USPQ2d at 1396. The “hypothetical person having ordinary skill in the art' to which the claimed subject matter pertains would, of necessity, have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988) disagreeing with the examiner' s definition of one of ordinary skill in the art (i.e. a doctorate level engineer or scientist working at least 40 hours per week in semiconductor research or development), and finding that the hypothetical person is not definable by way of credentials, and that the evidence in the application did not support the conclusion that such a person would require a doctorate or equivalent knowledge in science or engineering).
These hurdles render application of “a method of treatment of cancer” to a very high level of unpredictability. The lack of significant guidance from the present specification makes practicing the claimed invention unpredictable. Where the predictability in the art is low, the Applicant is required to provide greater disclosure and guidance to comply with the enablement requirement. MPEP § 2164.03.
(E) Existence of working examples & (F) Amount of direction or guidance by the inventor –
As previously established by Hanahan and Dass, cancer and triple negative breast cancer is a complex and sophisticated disease. Conversely, the specification does not demonstrate a means to treat this disease in subjects in need to the requirement of broadest reasonable interpretation. Instead, the instant specification only provides biochemical results. Therefore, the applicant has not provided sufficient guidance to enable one of skill in the art to make and use the claimed invention in a manner reasonably correlated with the scope of the claim.
(G) Quantity of experimentation needed to make or use the invention –
Taken together, the prior art demonstrates that the disease arises from multiple factors and etiologies. This covers a breadth and scope of material that is far from adequately addressed in the instant specification. While the specification demonstrates in vitro cell killing, it does not demonstrate how “a compound” would be able to matriculate into a new investigational drug with a reasonable chance of success to reach the status as a demonstrative drug containing therapeutically efficacious properties. Even if the compound was not being considered for human treatment, there are, established by J. M. McKim who emphasizes a truism of the pharmaceutical industry that persists to this day, is the failure of over 90% of promising new drug candidates due to unanticipated adverse effects or a lack of efficacy in humans, contrary to anticipated results based on prior biochemical cell, or animal models (introduction), introducing numerous hurdles that must be overcome for use in the broad category of a patient which is not a guaranteed, linear progression. This constitutes undue experimentation. Therefore, the lack of working examples commensurate in scope to the claimed invention and the unpredictability in successful application as described by claim 6, and as described in the specification, as filed, does not provide enablement for the claimed method of use.
In conclusion, the claimed invention does not provide enablement for the application in the method of use in treating the disease claimed. Thus, for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation is undue, due to the broad scope of the claim, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of ordinary skill in the art would be forced into undue experimentation to practice the claimed invention.
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
(New/Maintained) Claim 1 is rejected under 35 U.S.C. 103 as being unpatentable over Wen et al. (Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamid and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy, Eur. J. Med. Chem. 2016, 190, 350-359) in view of Le et al. (Novel 1-methyl-1H-pyrazole-5-carboxamide derivatives with potent anthelmintic activity, J. Med. Chem. 2019, 62, 3367-3380) and Miller et al. (Modulators of cystic fibrosis transmembrane conductance regulator, US 2016/0095858 A1, 2016).
Wen discloses structure 13g, where R = 3,4,5-trimethoxyphenyl and the disclosed adducts are alkyl. These structures are described as purposefully designed as HDAC inhibitors, with the most potent demonstrating IC₅₀ of 8 nM against all HDACs with specific preferences HDACs 1-3 and 6, for use as cytotoxic agents against cancer cells, identifying seven cell lines where hyper-acetylation of histone and non-histone proteins occurs, including in cell line MDA-MB-231 (pg. 354, table 3). Additionally, Wen demonstrates in vivo anti-tumor activity in HCT-116 xenografts (pg. 354, fig. 4).
Wen does not, however, disclose benzyl amide or sulfonamide adducts.
This deficiency is rectified by Le and Miller, Le who teaches the coupling of substituted benzylamines to pyrazole carboxylic acids using similar peptide coupling conditions. Miller teaches formation of sulfonamides from carboxylic acids.
As such, it would be prima facie obvious, to a person of ordinary skill in the art, before the effective filing date, to consider the core structure as disclosed by Wen containing 3,4,5-methoxyaryl pyrazoles, and forming adducts that explored a chemical space separate from alkyl substitutions. In particular, the biological target of interest is HDAC with a focus on cancer therapy, as outlined in the instant specification (para. 0126) where Applicant discloses their own HDAC inhibition assay along with an MTT assay on MDA MB 231 TBNC cells (para. 116). This is the same motivation as outlined by Wen.
Response to Arguments
The office kindly thanks the Applicant for their consideration and arguments to the previous office action. Responses are detailed below.
Applicant’s arguments, see pg. 14 – Claim Objections, filed 25 June 2026, with respect to claims 3 and 4 have been fully considered and are persuasive. The objections of claims 3 and 4 have been withdrawn.
Applicant’s cancellation of claim 4 is acknowledged.
On pgs. 14-15 – Rejections – 35 USC § 103, filed 25 June 2026, the Applicant argues:
… Applicant respectfully disagrees that the pending claims are obvious; however, in order to expedite prosecution of the current application Applicant has amended claim 1 to include features from the objected to dependent claim 2…
Applicant has misunderstood the rejection of claim 1 in the prior office action and identification of allowable subject matter in the now canceled claim 2. Claim 2 was considered to contain allowable subject matter because the Applicant demonstrates, in the instant specification, working in vitro examples of the compounds’ efficacy in MDA-MB-231 cells. Combining the limitation of claim 2 into independent claim 1 does not overcome the rejection as the prior art, as previously stated, discloses structurally similar compounds that are also efficacious in MDA-MB-231 cells utilizing the same biomechanical theory. The rejection of structural obviousness is presented because, while the specific structures are novel, the general structure does not introduce novelty that is significantly beyond what has already been described in the prior art. As Wen describes non-heteroaryl structures, to then move into the aryl-heteroaryl space does not appear to be, to the Examiner, a strategy underpinned by creativity but merely rather the next logical step in exploring the structural space as the core moieties are identical to the prior art.
Allowable Subject Matter
Claims 3 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base claim and any intervening claims.
Claim 5 is allowable.
Reasons For Allowance
The following is an examiner’s statement of reasons for allowance: the following is a statement of reasons for the indication of allowable subject matter: the structure defined by formula I were not taught in the prior art in a 100% embodiment. The closest matches are disclosed by Kamal et al. (Synthesis and anticancer activity of heteroaromatic linked 46-amido podophyllotoxins as apoptotic inducing agents, Bioorg. Med. Chem. Lett. 2013, 23, 273-280) including compounds 14a-i where R1 = R2 = R3 = OCH3. Wen et al. (Identification of N-(6-mercaptohexyl)-3-(4-pyridyl)-1H-pyrazole-5-carboxamide and its disulfide prodrug as potent histone deacetylase inhibitors with in vitro and in vivo anti-tumor efficacy, Eur. J. Med. Chem. 2016, 190, 350-359) discloses 13a-o where R = 3,4,5-trimethoxyphenyl in 13g, with an amide bond to a 6-carbon terminal alkyl halogen instead of the carboxylic acid, synthesized by peptide coupling. No examples beyond Wen were found to read upon the instant claims.
Several examples are disclosed where the Markush structures read upon the claimed structures. One such example is from Roberts et al. (Plasma kallikrein inhibitors for treatment of acute respiratory distress syndrome (ARDS) and related conditions, WO 2021/217053, 2021 October 28 publication). No disclosed specific examples were found to read upon the claimed structures.
Therefore, the prior art neither anticipates nor reasonably makes obvious the claimed invention and therefore, the claimed invention is deemed novel and unobvious over the prior art.
Any comments considered necessary by Applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claim 1 is rejected under 35 U.S.C. 103. Claim 6 is rejected under 35 U.S.C. 112(a). Claim 3 is objected to. Claim 5 is allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Allen Chao whose telephone number is (571)272-7001. The examiner can normally be reached Monday - Friday 0700-1300.
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/ALLEN CHAO/Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622
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